Cardiovascular disease (like atherosclerosis) represents the primary cause of mortality in developed countries. It has been shown that a lipid disorder, such as high blood cholesterol and triglycerides, increases the risk for atherosclerosis, and thus for heart disease, stroke, high blood pressure and other pathological conditions. One key strategy for reducing the risk of atherosclerosis has been to lower the blood cholesterol levels.
The most of the cholesterol found in humans is produced by the body. Cholesterol is unable to dissolve in the blood and must therefore be transported to and from cells by lipoprotein carriers. Low-density lipoprotein (LDL) is known as “bad” cholesterol. High-density lipoprotein (HDL) is known as “good” cholesterol. These two types of lipids, along with triglycerides and Lp(a) cholesterol, make up the total blood cholesterol count. An elevated LDL blood cholesterol level (hypercholesterolemia) may lead to slow build up cholesterol deposits in the walls of the arteries feeding the heart and brain, forming a plaque which can clog these arteries, a condition known as atherosclerosis. A clot (thrombus) that forms near this plaque can block the blood flow to a part of the heart muscle and cause a heart attack. As well as if such a clot blocks the blood flow to a part of the brain, a stroke results.
Cholesterol levels in many people can be controlled by diet, but for many patients diet changes alone are insufficient to reduce high cholesterol. Treatment options may include lipid-regulating medications, such as statins (simvastatin, atorvastatin), that act to lower LDL cholesterol. These drugs, however, are associated with significant adverse side effects. Additional therapies may include the use of lipid-lowering compounds such as ezetimibe that selectively inhibit the intestinal cholesterol absorption (WO9508532; Rosenblum et. al. J. Med. Chem. 1998, 41, 973).
Ezetimibe analogues have also been reported to inhibit the cholesterol absorption (Xu et. al. Bioorg. Med. Chem. Lett. 2007, 17, 101).
Several other 2-azetidinone derivatives have been reported as being useful in lowering cholesterol.
EP1522541A1 discloses heterocyclic compounds including 2-azetidinones useful in the treatment and prevention of atherosclerosis and for the reduction of cholesterol levels. U.S. Pat. No. 7,470,678B2 discloses diphenylazetidinone derivatives for treating disorders of the lipid metabolism. U.S. Pat. No. 5,767,115A relates to hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents.
Although it has been proved that ezetimibe decreases cholesterol levels, its efficacy on decreasing atherosclerotic or vascular events remains questionable. (Mitka M (May 2008). “Cholesterol drug controversy continues”. JAMA 299 (19): 2266).
Therefore, there remains a need for additional safer and more effective therapeutics to lower cholesterol as a way to prevent and/or treat cardiovascular diseases and conditions.